Hand-held phase-shift detector for sensor applications

ABSTRACT

The invention is directed to a novel phase-shift detector capable of interfacing with an array of sensors. The detector is light-weight, portable and capable of fitting within the palm of a hand. The detector may be used in conjunction with a variety of diagnostic, biosensor and chemical sensor applications.

STATEMENT OF GOVERNMENT INTEREST

This invention was reduced to practice with Government support under Grant No. R01 EB000720 awarded by the National Institutes of Health and Grant No. CHE-0442100 awarded by the National Science Foundation; the Government is therefore entitled to certain rights to this invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a portable hand-held phase-shift detector capable of interfacing with piezoelectric microcantilever sensors (PEMS) and methods for using the detector and a system including the detector. The invention is particularly useful as a sensor or diagnostic device.

2. Description of the Related Technology

Biosensors and chemical sensors coupled with impedance analyzers are well known in the art. For example, U.S. Pat. No. 6,278,379 and U.S. publication nos. 20060257286 and 20060217893 discloses sensor systems incorporating an impedance analyzer to detect changes in resonance frequency.

Current impedance analyzers, however, are typically bulky, heavy and relatively immobile, thereby limiting the circumstances in which resonance frequency may be measured. Although some impedance analyzers, such as impedance analyzers for determining the physical properties of large structures such as a building and impedance analyzers for determining body composition have been made portable, as disclosed by U.S. patent application publication no. 2005/0114045 and U.S. Pat. No. 6,280,396, impedance analyzers for use with chemical sensors or biosensors remain large, cumbersome and relatively immobile.

Therefore there is a need to develop a light, portable, hand-held detector to facilitate diagnostic or sensor applications.

SUMMARY OF THE INVENTION

The invention is directed to a novel phase-shift detector capable of interfacing with an array of sensors.

In one aspect of the invention, the phase-shift detector is lightweight and portable.

In another invention, the phase-shift detector is a hand-held device capable of fitting within the palm of a hand.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1( a) is a schematic of the hand-held phase detector, oscillator, phase detector and relay component.

FIG. 1( b) is a photograph of the hand-held phase shift detector interfaced with an array of detectors for Bacillus anthracis spores.

FIG. 2( a) is a schematic of a hand-held phase-shift detector working with an array of PEMS capable of simultaneous detection of multiple antigens.

FIG. 2( b) is a photograph of a hand-held, portable phase-shift detector

FIG. 2( c) an optical micrograph of an array of four lead-magnesium niobate-lead titanate solid solution (PMN-PT)/Cu PEMS.

FIG. 3 is a graph of resonance frequency shift versus time showing the detection of Bacillus anthracis spores using a hand held phase-shift detector.

FIG. 4( a) is a graph of resonance frequency versus time showing the simultaneous detection of three PEMS, one coated with scFv of HER2, one coated with PSA antibodies and one coated with gp120 antibodies in a 23 μg/ml HER2 solution.

FIG. 4( b) is a graph of resonance frequency versus time showing the simultaneous detection of three PEMS, one coated with scFv of HER2, one coated with PSA antibodies and one coated with gp120 antibodies in an 18 μg/ml PSA solution.

FIG. 4( c) is a graph of resonance frequency versus time showing the simultaneous detection of three PEMS, one coated with scFv of HER2, one coated with PSA antibodies and one coated with gp120 antibodies in a 100 μg/ml gp120 solution.

FIG. 5 is a graph of resonance frequency versus time showing a unique DMMP detection pattern.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention is directed to a portable hand-held phase-shift detector 1, capable of simultaneously interfacing with and monitoring one or more sensors 7, as shown in FIGS. 1( a) and 1(b). Phase-shift detector 1 comprises an oscillator 2, a phase detector 3, a relay component 4 and a display screen 5. The relay component 4 rotates the connection of phase detector 3 and oscillator 2 among the connected sensors 7 in the sensor array to enable phase detector 3 to measure the output of each sensor 7.

Oscillator 2 comprises a resonance circuit, including a transmission line, a circuit substrate, chip components mounted on the circuit substrate, and an amplifying circuit for amplifying a resonance signal generated by the resonance circuit. Connected to sensors 7 by a connection 6, oscillator 2 generates an input signal or voltage to actuate sensors 7. Oscillator 2 preferably actuates sensors 7 by inducing oscillation of sensors 7 in a frequency range that encompasses the resonance frequencies of sensors 7 to enable detection of resonance frequency shift of sensors 7 resulting from analyte binding.

Phase detector 3 measures the magnitude and phase shift of the output voltage of sensors 7 through a connection 8. A maximum in the phase shift plotted versus frequency identifies the resonance frequency. A significant shift in resonance frequency indicates the binding of a particular compound or molecule to the specific receptor on a sensor surface, and thereby, verifies the presence of said compound or molecule in the environment being tested.

In one embodiment, oscillator 2 may be a microprocessor-controlled signal generator. Phase-shift detector 1 may optionally include a display screen 5 for displaying results in any suitable manner such as in a numerical or graphical format. In a preferred embodiment, phase-shift detector 1 may also include a data transmitter for transmitting data to an electronic information storage medium such as a computer or computer disk. Display screen 5, or other suitable means, may function as an indicator which provides an indication of the presence of a specific analyte. Alternatively, display screen 5 or other suitable means may function as an indicator which provides an indication if a specific analyte is present in an amount which exceeds a threshold value.

As shown in FIG. 1( b), portable hand-held phase-shift detector 1 may be incorporated in, or work in conjunction with, any suitable sensor system. In a preferred embodiment, phase-shift detector 1 is associated with one or more piezoelectric microcantilevers (PEMS) or piezoelectric micro-disks and enables detection of the magnitude and phase shift of an output voltage of each PEMS. Phase-shift detector 1 may be powered by any standard power source. In a preferred embodiment, the power source is portable, small and lightweight, such as a typical 9 volt battery. Hand-held phase-shift detector unit 1 may be about 3.5 inches by 7.5 inches in size. Preferably, phase-shift detector unit 1 may be simultaneously connected to a plurality of sensors. In a preferred embodiment, phase-shift detector unit 1 is simultaneously connected to from about eight sensors to about thirty-two sensors. Preferably, the entire system is sufficiently small to be carried by a single person to a site of detection.

In a preferred embodiment, the hand-held phase shift detector 1 has dimensions of up to about 7.5 cm deep by about 30 cm high by about 30 cm wide and weight of no more than about 2 kg and may simultaneously operate as many as 32 sensors. The array sensors and their holder may be no larger than about 2 cm in width, about 2 cm in depth, and about 1 cm in height and weigh no more than 50 g. The phase-shift detector 1 may further include a relay mechanism, such as a ribbon cable, for facilitating connection 6 and connection 8. Preferably, the ribbon cable is less than 1 m long, less than 3 cm wide, and weighs less than 50 g. Preferably, the total weight of the system including hand held phase shift detector 1 and sensors 7 is not more than 2.5 kg.

Advantageously small, the device is both portable and robust. In a preferred embodiment, the device may fit within the palm of a hand. Since the phase-shift detector is simple in design, it may be easily and inexpensively manufactured and may be made available as an off-the-shelf product for numerous applications. The phase-shift detector may be used in biosensor, diagnostics or any molecular or chemical sensor applications.

EXAMPLES Example 1

FIG. 2( b) shows one embodiment of a phase-shift detector, comprising an Analog Devices AD8203 RF gain/phase detector IC as the measuring device and an Analog Devices AD9850 DDS Frequency Synthesizer as a high resolution microprocessor-controlled signal generator, in combination with an array of PEMS. The phase-shift detector of FIG. 2( a) is capable of monitoring at least 8 PEMS at the same time.

Example 2

FIG. 1( b) shows a phase-shift detector and an array of PEMS. The hand-held phase shift-detector accurately detected the frequency shift of each PEMS. FIG. 3 shows the results of an experimental study for detecting Bacillus anthracis (BA) processed with the phase-shift detector of FIG. 1( b). The open circles represent PZT/glass PEMS with a 2 mm long glass tip coated with antibody specific to BA spores, and the open squares represent cantilevers coated with antibody specific to S. typhimurium and not specific to BA spores. The phase-shift detector accurately reported that the PEMS identified the presence of BA spores from only the PEMS coated with antibodies specific to BA spores; by comparison, the PEMS coated with antibodies specific to Salmonella did not detect the BA spores. The results therefore demonstrate that the hand-held phase-shift detector is capable of generating accurate results similar to those obtained by an impedance analyzer.

Example 3

A hand-held phase-shift detector in combination with an array of 3 PEMS was used to detect the presence of various antigens. Each PEMS had a different receptor immobilized on its surface including, anti-gp120, anti-PSA, and scFv of Her2. gp120 is a surface protein on human immunodeficiency viruses (HIV). PSA (prostate specific antigen) is a prostate cancer marker, and HER2 is a member of the epidermal growth factor receptor linked to breast cancer and other cancers and scFv is an engineered single-chain variable fragment receptor.

The PEMS were placed in 3 different solutions, each containing an antigen specific to each receptor. As shown in FIG. 4, the phase-shift detector correctly reported that only the PEMS having the antigen specific receptor corresponding to the marker present in the solution responded when the array was submerged in each solution. FIG. 4( a) shows that only the PEMS with scFv to HER2 responded to HER2. FIG. 4( b) shows that only the PEMS with antibodies to PSA responded to PSA, and FIG. 4( c) shows that only the PEMS with antibodies to gp120 responded to gp120. This experiment clearly illustrates that the phase-shift detector and PEMS array are capable of simultaneously detecting multiple antigens.

Example 4

The hand-held phase-shift detector, in combination with a PEMS array, may also be used to detect gases/chemicals. Unlike biological detection where antibody-antigen binding is specific, most receptors for gas/chemical detection are not selective. By using a PEMS array having different receptors, it is possible to create a customized detection pattern for a gas or chemical. The custom combination of the PEMS array increases detection sensitivity and the accuracy of chemical or gas detection. FIG. 5 shows a unique PEMS array for dimethyl methylphosphonate (DMMP), a nerve gas simulant.

Three lead magnesium niobate-lead titanate solid solution (PMN-PT)/Cu PEMS are each coated with a different receptor which is immobilized on the PEMS surface by microporous silica, mesoporous alumina and a monolayer of Cu²⁺ ions on a self-assembled monolayer of 11-mercaptoundecanoic acid (MUA) to detect DMMP.

Having described the preferred embodiments of the invention which are intended to be illustrative and not limiting, it is noted that modifications and variations can be made by persons skilled in the art in light of the above teachings. It is therefore to be understood that changes may be made in the particular embodiments of the invention disclosed which are within the scope and spirit of the invention as outlined by the appended claims. Having thus described the invention with the details and particularity required by the patent laws, the intended scope of protection is set forth in the appended claims. 

The invention claimed is:
 1. A portable device for detecting a phase shift comprising: an oscillator for generating an input signal at a desired frequency, a connection to said oscillator capable of providing an operative connection of said oscillator to at least one sensor to induce oscillation of said sensor, and a phase detector capable of detecting a phase shift between an initial output voltage from said at least one sensor induced by said oscillation of said sensor prior to exposure to a sample and an output voltage from said at least one sensor induced by said oscillation upon exposure of said at least one sensor to the sample.
 2. The device of claim 1, wherein the device is capable of being operatively connected to an array of multiple sensors.
 3. The device of claim 2, further comprising a relay for selectively connecting said phase detector to each of said sensors for selective receipt of the output voltage from that sensor.
 4. The device of claim 1, wherein the oscillator is a microprocessor controlled signal generator.
 5. The device of claim 3, wherein the sensors are selected from the group consisting of: piezoelectric microcantilevers and piezoelectric microdisks.
 6. The device of claim 1, wherein the phase detector is an RF gain/phase detector.
 7. The device of claim 1, wherein the total weight of the device is not more than about 2 kg.
 8. The device of claim 1, wherein the device has a size of not more than about 7.5 cm in depth, by 30 cm in width and 30 cm in height.
 9. The device of claim 1, further comprising an indicator that generates an indication of the presence of an analyte.
 10. The device of claim 1, further comprising an indicator that generates an indication of the presence of an amount of an analyte that exceeds a threshold amount.
 11. A portable system for detecting the presence of an analyte comprising: an oscillator for generating an input signal at a desired frequency, at least one sensor capable of generating an initial output voltage when provided with an input signal, a connection from said oscillator to said at least one sensor for providing said input signal to said sensor from said oscillator to induce oscillation of said sensor, a phase detector capable of detecting a phase shift between the initial output voltage from said at least one sensor induced by said oscillation of said sensor prior to exposure to a sample and an output voltage from said at least one sensor induced by said oscillation upon exposure of said at least one sensor to the sample, and a connection from said sensor to said detector for providing said voltage signal from said sensor to said detector, wherein said system is sufficiently small to be carried by a single person to a site of detection.
 12. The system of claim 11, comprising multiple sensors, a connection from said oscillator to each sensor and a connection from each sensor to said detector.
 13. The system of claim 12, further comprising a relay for selectively connecting said detector to each of said sensors for selective receipt of the output voltage from that sensor.
 14. The system of claim 13, wherein the sensors are piezoelectric microcantilevers.
 15. The system of claim 11, wherein the oscillator is a microprocessor controlled signal generator.
 16. The system of claim 11, wherein the phase detector is an RF gain/phase detector.
 17. The system of claim 11, wherein the total weight of the system is not more than about 2.5 kg.
 18. The system of claim 11, wherein the system has a size of not more than about 7.5 cm in depth, by 30 cm in width and 30 cm in height.
 19. The system of claim 11, further comprising an indicator that generates an indication of the presence of an analyte.
 20. The system of claim 11, further comprising an indicator that generates an indication of the presence of an amount of an analyte that exceeds a threshold amount. 